Fibrosis is a response to chronic liver disease that results in excessive accumulation of extracellular matrix proteins and formation of scar tissue. Fibrosis represents a clinical challenge of ...worldwide significance. Several studies have demonstrated that many natural products and herbal medicines have activity against liver fibrosis, and extracts of milk thistle such as silymarin and silybin are the natural compounds most commonly prescribed for liver diseases. Therefore, we sought to assess and compare the pharmacokinetic properties and bioavailability of silybin-phosphatidylcholine complex in oily-medium soft-gel capsules and conventional silymarin tablets in healthy Mexican volunteers.
We enrolled 23 healthy volunteers to participate in a prospective, balanced, blind, single-dose, two-way crossover study with a one-week washout period. Fasting participants received either 45 mg silybin-phosphatidylcholine complex or 70 mg silymarin to assess which formulation provided better bioavailability of silybin. Plasma was obtained and analysed for silybin concentration using a validated ultra-performance liquid chromatography-tandem mass spectroscopy method. Pharmacokinetic parameters were obtained by non-compartmental analysis and values were compared by analysis of variance for a crossover design. Ratios of maximum plasma drug concentration and area under the curve (AUC) were obtained and 90% confidence intervals were calculated.
The 23 healthy subjects (11 women, 12 men) who participated in the study were aged 22-31 years old (average: 28), average weight 64.8 kg, height 1.65 m and body mass index 23.5 kg/m
. Plasma levels of silybin were higher after the administration of silybin-phosphatidylcholine complex capsules compared with that after conventional silymarin tablets (P < 0.0001).
The silybin-phosphatidylcholine complex in oily-medium soft-gel capsules seems to provide superior bioavailability. However, clinical studies must be performed to demonstrate its clinical relevance in the treatment of liver diseases.
NCT03440164 ; registered on November 11, 2016.
Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H
S) is involved in diabetes-induced hyperalgesia and allodynia. ...However, the molecular target through which H
S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H
S-induced hyperalgesia in diabetic rats.
Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H
S, 3-100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3-3 µg/paw), HC-030031 (100-316 µg/paw) and SKF-96365 (10-30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3-30 µg/paw), HC-030031 (100-1000 µg/paw) and SKF-96365 (10-100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-β-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons.
Our data suggest that H
S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy.
Painful peripheral neuropathy can be associated with nerve damage caused by diabetes mellitus. Although pregabalin is the first-line therapy for peripheral neuropathy, it shows substantial ...discontinuation rates, mainly because of nervous system side effects as motor incoordination. Multimodal therapy may improve the motor side effect profile of pregabalin. The aim of this study was to evaluate the interaction of pregabalin + thioctic acid or pregabalin + α-tocopherol on allodynia and motor performance in neonatal streptozotocin-induced diabetic rats. Efficacy of drugs separately or in combination was tested by tactile allodynia using von Frey filaments. Isobolographic and interaction index analysis were used to determine the antiallodynic interaction between pregabalin and either thioctic acid or α-tocopherol. Motor performance was measured using a rotarod test. Pregabalin, thioctic acid, and α-tocopherol reduced, in a dose-dependent fashion, tactile allodynia. Pregabalin + thioctic acid and pregabalin + α-tocopherol combinations also dose-dependently reduced allodynic behavior in diabetic rats. Isobolographic analysis revealed an additive interaction for both combinations. Consistently, the interaction indices confirmed the additive effect between pregabalin + thioctic acid and pregabalin + α-tocopherol. In addition, the administration of either combination improved motor incoordination induced by pregabalin. Data suggests that thioctic acid or α-tocopherol could positively impact the therapeutic profile of pregabalin, because they might be useful for reducing motor incoordination associated to pregabalin in patients with peripheral neuropathy.
•Antiretroviral-experienced human immunodeficiency virus (HIV)–positive Mexican individuals have suboptimal zinc dietary intake; suboptimal dietary intake of selenium is less common.•Patients in this ...study had deficient serum concentrations of zinc and selenium.•Zinc could play a role in muscle mass preservation; whereas selenium may play a role in bone health and modulating HIV-associated chronic inflammation.
Micronutrient deficiencies are common among people living with HIV (PLWHIV). The clinical and immunologic consequences of micronutrient deficiencies have been poorly explored in the context of human immunodeficiency virus (HIV) infection. The aim of this study was to determine the prevalence of zinc and selenium deficiency (dietary intake and serum concentrations) and analyze their associations with absolute CD4+ T-cell counts, inflammation markers, and metabolic disorders in a cohort of antiretroviral-experienced HIV-infected individuals.
The zinc and selenium intakes of 124 HIV-infected men were estimated using 3-d food records. In a subcohort of 45 individuals, serum zinc and selenium concentrations and proinflammatory cytokines were determined. Body composition, bone mineral density (BMD), CD4+ T-cell counts, lipid profile, glucose, and blood pressure were determined and were associated with zinc and selenium dietary intake and serum concentrations.
Of the PLWHIV studied, 58% had suboptimal intake of zinc and 8% demonstrated suboptimal intake of selenium. Serum deficiencies for zinc and selenium were 23.9% and 65.9%, respectively. Zinc and selenium intake were correlated with increased muscle mass. Selenium intake was associated with increased BMD of the lumbar region. An inverse correlation between serum selenium concentration and several proinflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) was found.
Suboptimal zinc and selenium intake and serum concentration deficiencies are highly prevalent in treated HIV-positive individuals and are associated with body composition, BMD, and inflammation. Clinical trials should be designed to explore the effect of zinc and selenium supplementation on metabolic, inflammatory, and immunologic parameters on the HIV-positive population.
The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction ...between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered
, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (
) did not differ from the experimental effective dose 40 (
) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student′s
-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of
mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors.
The aim of the present study was to determine whether tizanidine, an alpha2-adrenoceptor agonist, is able to increase the anti-inflammatory and anti-nociceptive effects of naproxen and ketorolac with ...a low incidence of gastric injury and spontaneous activity in rats. The anti-inflammatory effect was assayed in a carrageenan test, and oral administration of tizanidine (ED40 =0.94±0.2mg/kg), naproxen (ED40=3.18±0.4mg/kg), and ketorolac (ED40=16.4±1.9mg/kg) showed a dose-dependent effect on inflammation. The anti-nociceptive effect was assayed in the formalin test, and administration of tizanidine (ED40=0.39±0.06mg/kg, p.o.), naproxen (ED40=33.9±3.9mg/kg, p.o.) or ketorolac (ED40=6.49±1mg/kg, p.o.) each showed a dose-dependent anti-nociceptive effect. The effects of combinations of tizanidine/naproxen and tizanidine/ketorolac were determined considering their ED40 at a rate of 1:1. Additionally, the tizanidine/naproxen and tizanidine/ketorolac combinations showed anti-inflammatory and anti-nociceptive effects. The tizanidine/ketorolac combination was more potent than tizanidine/naproxen, in both inflammatory (interaction index=0.03 tizanidine/ketorolac and 0.07 tizanidine/naproxen) and nociceptive (interaction index=0.005 tizanidine/ketorolac and 0.01 tizanidine/naproxen) processes. In both cases, tizanidine improved naproxen and ketorolac gastrointestinal tolerability by 50%. Furthermore, co-administration of tizanidine with naproxen or ketorolac did not modify the spontaneous activity in the same way as individual tizanidine administration. Considering that tizanidine increases the anti-inflammatory and anti-nociceptive effects of naproxen or ketorolac, with an increase in gastric tolerability, tizanidine could provide therapeutic advantages in the clinical treatment of inflammation and pain.
The aim of this study was to investigate the antinociceptive potential of (−)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin ...tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (−)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (−)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonistsmethiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (−)-epicatechin was also prevented by the intraperitoneal administration of L-NAME nitric oxide (NO) synthase inhibitor, 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4-aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large-conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (−)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.
Drug combinations are being studied as potential therapies to increase the efficacy or improve the safety profile of weight loss medications. This study was designed to determine the anorectic ...interaction and safety profile of 5-hydroxytryptophan (5-HTP)/carbidopa + diethylpropion and 5-HTP/carbidopa + phentermine combinations in rats. The anorectic effect of individual drugs or in combination was evaluated by the sweetened milk test. Isobologram and interaction index were employed to determine the anorectic interaction between 5-HTP/carbidopa and diethylpropion or phentermine. Plasma serotonin (5-HT) was measured by ELISA. Safety of repeated doses of both combinations in rats was evaluated using the tail sphygmomanometer, cardiac ultrasound, hematic biometry and blood chemistry. A single oral 5-HTP, diethylpropion or phentermine dose increased the anorectic effect, in a dose-dependent fashion, in 12 h-fasted rats. A dose of carbidopa at 30 mg/kg reduced the 5-HTP-induced plasmatic serotonin concentration and augmented the 5-HTP-induced anorectic effect. Isobologram and interaction index indicated a potentiation interaction between 5-HTP/30 mg/kg carbidopa + diethylpropion and 5-HTP/30 mg/kg carbidopa + phentermine. Chronic administration of experimental ED40 of 5-HTP/30 mg/kg carbidopa + phentermine, but not 5-HTP/30 mg/kg carbidopa + diethylpropion, increased the mitral valve leaflets area. Moreover, there were no other significant changes in cardiovascular, hematic or blood parameters. Both combinations induced around 20% body weight loss after 3 months of oral administration. Results suggest that 5-HTP/30 mg/kg carbidopa potentiates the anorectic effect of diethylpropion and phentermine with an acceptable safety profile, but further clinical studies are necessary to establish their therapeutic potential in the obesity treatment.
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